The Role of Insulin-like Growth Factor Binding Proteins in Articular Cartilage. Insulin-like growth factor-1 (IGF-1) is an important anabolic/homeostatic factor for articular cartilage matrix metabolism. The sensitivity of cartilage to this growth factor decreases with age, and it has been suggested that this is related to changes in IGF-binding proteins (IGF-BPs). The latter form a versatile regulatory system that can agonize with or antagonize IGF action. Importantly, there are recent reports that IGF-BP mRNAs are increased during human osteoarthritis (OA), and that increased levels of IGF-BPs are released from cultured OA chondrocytes, as compared to normal age-matched controls. The working hypothesis of this investigation is that in normal cartilage, IGF-BP-2 enhances the actions of IGF, while IGF-BP-6 antagonizes them, and that the nature and balance of the agonistic and antagonistic IGF-BPs changes during aging and OA. The specific aims of the present feasibility study are: 1] To develop molecular biological methods, specifically antisense oligodeoxynucleotide (ODN) techniques, to inhibit IGF-BP expression in articular cartilage. The proposed studies will test antisense ODNs to IGF-BP-2 in a well characterized bovine articular cartilage system. It is expected that these model studies will serve as a departure point to launch an in-depth investigation of the role of IGF-BP-2 and other IGF-BPs in matrix metabolism in bovine and human cartilage. 2] To initiate systematic studies to analyze IGF-BPs during aging and osteoarthritis in human cartilage. Proteins will be directly extracted from fresh articular cartilages and analyzed by methods previously developed by the P.I. It is proposed that in the long term, these studies will lead to a better understanding of the mechanisms underlying the response of cartilage to IGF and that this information will facilitate the development of rational protocols to optimize IGF and matrix function in aging and OA cartilage.